Varicella-zoster virus (VZV) establishes latency in human sensory and cranial nerve ganglia during primary infection (varicella), and the virus can reactivate and cause zoster after primary infection. The mechanism of how the virus establishes and maintains latency and how it reactivates is poorly understood, largely due to the lack of robust models. The varicella vaccine virus, termed vaccine Oka VZV, was derived from a strain of wild-type VZV, termed parental Oka VZV. We found that infection of neurons at the axonal site with cell-free parental Oka VZV resulted in latent infection with inability to detect several viral mRNAs by reverse transcriptase-quantitative PCR, no production of infectious virus, and maintenance of the viral DNA genome in an endless configuration, consistent with an episome configuration. With deep sequencing, however, multiple viral mRNAs were detected. Treatment of the latently infected neurons with antibody to nerve growth factor resulted in production of infectious virus in about 25% of the latently infected cultures. Infection of neurons at the axonal site with vaccine Oka VZV resulted in a latent infection similar to infection with parental Oka VZV; however, in contrast to parental Oka VZV, vaccine Oka-infected neurons were markedly impaired for reactivation after treatment with antibody to nerve growth factor. In addition, viral transcription was markedly reduced in neurons latently infected with vaccine Oka VZV compared with parental Oka VZV. Our in vitro system recapitulates both VZV latency and reactivation in vivo and may be used to study viral vaccines for their ability to establish latency and reactivate. VZV can reactivate to cause zoster and the latter can be complicated by postherpetic neuralgia (PHN), a debilitating chronic pain condition. Based on previous studies identifying a causative role for anti-cytokine autoantibodies in patients with opportunistic infections, we determined if some cases of PHN might be associated with anti-cytokine antibodies. Sera from herpes zoster (HZ) patients without and with PHN were examined for the presence of autoantibodies against multiple cytokines; as a control, a cohort of patients with complex regional pain syndrome or neuropathic pain not due to PHN was tested for autoantibodies against cytokines. Six patients (out of 83) with PHN had markedly elevated levels of autoantibodies against interferon-alpha, interferon-gamma, GM-CSF, or interleukin-6. In contrast, the 115 HZ patients without PHN and those in the pain control group showed low or no autoantibodies, respectively, against these four cytokines. In vitro functional testing revealed that three of the five anti-cytokine autoantibody positive PHN subjects had neutralizing autoantibodies against interferon-alpha, GM-CSF, or interleukin-6. In contrast, none of the HZ patients without PHN had neutralizing autoantibodies. These results suggest the possibility that sporadic anti-cytokine autoantibodies in some subjects may cause an autoimmune immunodeficiency syndrome leading to uncontrolled VZV reactivation, nerve damage and subsequent PHN.